safety of ruti® vaccination in mdr-tb patients

Conditions: Tuberculosis, Multidrug Resistant

Summary: prospective, randomized, double-blind, multicentre, placebo-controlled clinical phase iia trial to evaluate safety and immunogenicity of ruti® vaccine in multidrug-resistant tuberculosis (mdr-tb) patients favourably responding to standard mdr-tb treatment. time point of vaccination starts at 16 weeks upon start of standard mdr-tb treatment (cohort a), and if clinically safe as evaluated by an independent panel of experts (dsmb), another cohort of patients will be vaccinated at 2 weeks upon start of standard mdr-tb treatment (cohort b), all the patients will be followed up 8 weeks after vaccination.

prospective, randomized, double-blind, multicentre, placebo-controlled clinical phase iia trial to evaluate safety and immunogenicity of ruti® vaccine in multidrug-resistant tuberculosis (mdr-tb) patients favourably responding to standard mdr-tb treatment. time point of vaccination starts at 16 weeks upon start of standard mdr-tb treatment (cohort a), and if clinically safe as evaluated by an independent panel of experts (dsmb), another cohort of patients will be vaccinated at 2 weeks upon start of standard mdr-tb treatment (cohort b)

Eligibility criteria:
inclusion criteria in order to be eligible to participate in this study, a subject must meet all of the following criteria: * diagnosed with pulmonary mdr-tb, and therefore managed with second line tb drugs; * admitted in a tb unit / hospital routinely diagnosed with pulmonary mdr-tb with clinical status ≥ 6 with bandim tb score combined with chest radiography; and microbiological criteria according to the medical history), using rapid genetic testing (genexpert tb test) and mgit to confirm or line probe assay; or classical diagnostic tools including sputum microscopy and culture followed by phenotypic drug susceptibility testing. all of this medical information will be in the medical history; * females and males aged ≥ 18; females of non-childbearing potential: at least 2 years post-menopausal or surgically sterile (e.g. tubal ligation); females of childbearing potential (including females less than 2 years post-menopausal) must have a negative pregnancy test at enrolment and must agree to use highly effective methods of birth control (i.e. diaphragm plus spermicide or male condom plus spermicide, oral contraceptive in combination with a second method, contraceptive implant, injectable contraceptive, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in the study and for 30 days after end of the study for each group; males must agree to use a double barrier method of contraception (condom plus spermicide or diaphragm plus spermicide) while participating in the study and for 30 days after end of the study for the respective group; or the male patient or his female partner must be surgically sterile (e.g. vasectomy, tubal ligation) or the female partner must be post-menopausal; * the patient must provide written informed consent; * the patient must be willing and able to attend all study visits and comply with all study procedures. inclusion criteria for vaccination * having successfully completed 16, 8 or 4 weeks (depending on the cohort) of mdr-tb treatment, fully supervised, and * with beneficial initial response to therapy, evidenced by: clinical response criteria: patients admitted in a tb unit / hospital routinely diagnosed with pulmonary mdr-tb (according to clinical status ≤ 5 with bandim tb score) (33). transient deterioration of chest radiographic abnormalities might be explained by a paradoxical inflammatory response, and this may therefore not necessarily be interpreted as treatment failure; such decision depends on consensus with the dsmb; evidence of improvement on chest x-ray. • microbiological response criteria: it has to be reported a reduction of the bacillary load in the sputum by means of the reduction of bacillary counts in genexpert tb test and liquid culture (mgit) to confirm (diagnosis week 0 collected in the medical history) at week 4 in cohortsc, week 8 in both cohorts (a-b) and week 12 and 16 in cohort a. exclusion criteria a potential subject who meets any of the following criteria will be excluded from participation in this study: * inability to provide written informed consent; * women reported, or detected, or willing to be pregnant during the trial period; * severity of illness precluding full evaluation: expected early death, evidenced by respiratory failure, low blood pressure, who performance score 3-4; central nervous system involvement of tb (tb meningitis, intra-cranial tuberculomas) as there is too little evidence for effective drug penetration for second-line tb drugs; * major co-morbid conditions precluding full evaluation, i.e., active lung cancer, acute coronary syndrome, heart failure exceeding nyha class 2; a diagnosis of metastasized malignancy; renal failure in excess of creatinine clearance \ 30 kg/m2); chronic liver disease - child-pugh class c; * any of the following laboratory parameters: aspartate aminotransferase (ast) or alanine aminotransferase (alt) \> 3 x upper limit of normal (uln) total bilirubine \> 2 x uln neutrophil count ≤ 500 neutrophils / mm3 platelet count \< 50,000 cells / mm3 * receiving or anticipated to receive a daily dose of ≥ 10 mg of systemic prednisone or equivalent within the period starting 14 days prior to enrolment. note: patients are allowed to receive an acute, short course of methylprednisolone or prednisone or equivalent for management of an acute exacerbation of copd or reactive airway disease in asthmatics; * cytotoxic chemotherapy or radiation therapy within the previous 3 months; * hiv co-infection, if cd4 count \ 250 copies/ml are expected to be able to mount a sufficient cellular immune response and will therefore be eligible; * blood transfusion in the last three weeks prior to the trial; * documented allergy to tb vaccines, notably, to the ruti® vaccine.